Abstract
Clostridium (Clostridioides) difficile, a Gram-positive, anaerobic bacterium, is the leading single cause of nosocomial infections in the United States. A major risk factor for Clostridium difficile infection (CDI) is prior exposure to antibiotics, as they increase susceptibility to CDI by altering the membership of the microbial community enabling colonization. The importance of the gut microbiota in providing protection from CDI is underscored by the reported 80 to 90% success rate of fecal microbial transplants in treating recurrent infections. Adaptive immunity, specifically humoral immunity, is also sufficient to protect from both acute and recurrent CDI. However, the role of the adaptive immune system in mediating clearance of C. difficile has yet to be resolved. Using murine models of CDI, we found that adaptive immunity is dispensable for clearance of C. difficile However, random forest analysis using only two members of the resident bacterial community correctly identified animals that would go on to clear the infection with 66.7% accuracy. These findings indicate that the indigenous gut microbiota independent of adaptive immunity facilitates clearance of C. difficile from the murine gastrointestinal tract.IMPORTANCEClostridium difficile infection is a major cause of morbidity and mortality in hospitalized patients in the United States. Currently, the role of the adaptive immune response in modulating levels of C. difficile colonization is unresolved. This work suggests that the indigenous gut microbiota is a main factor that promotes clearance of C. difficile from the GI tract. Our results show that clearance of C. difficile can occur without contributions from the adaptive immune response. This study also has implications for the design of preclinical studies testing the efficacy of vaccines on clearance of bacterial pathogens, as inherent differences in the baseline community structure of animals may bias findings.
Highlights
Clostridium (Clostridioides) difficile, a Gram-positive, anaerobic bacterium, is the leading single cause of nosocomial infections in the United States
Cohousing normalized the WT and RAG1Ϫ/Ϫ mouse fecal communities such that they were not significantly different (ANOSIM P ϭ 0.087) (Fig. 1A). Both groups of mice were pretreated with antibiotics, separated into cages based on genotype, and challenged with C. difficile strain 630
Reanalyzing the preantibiotic microbial communities by cohousing group rather than genotype, we found that the mice that eventually cleared C. difficile had significantly distinct community compared to the mice that remained colonized (ASOSIM P ϭ 0.047) (Fig. 1C)
Summary
Clostridium (Clostridioides) difficile, a Gram-positive, anaerobic bacterium, is the leading single cause of nosocomial infections in the United States. A major risk factor for Clostridium difficile infection (CDI) is prior exposure to antibiotics, as they increase susceptibility to CDI by altering the membership of the microbial community enabling colonization. Random forest analysis using only two members of the resident bacterial community correctly identified animals that would go on to clear the infection with 66.7% accuracy These findings indicate that the indigenous gut microbiota independent of adaptive immunity facilitates clearance of C. difficile from the murine gastrointestinal tract. Other than microbiome-mediated prevention of colonization, adaptive immunity is sufficient to provide protection from both acute and recurrent CDI likely via antibody-mediated neutralization of C. difficile toxins TcdA and TcdB [11,12,13,14]. The role of the adaptive immune system in modulating C. difficile colonization has yet to be resolved
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